酸胺縮合：好搭檔TCFH/NMI的工藝案例

  • 2024-06-29 08:01
  • 原料藥合成工藝開發
苯胺親核性不好，用於酸胺縮合反應，酰氯法偏多，其他縮合劑法也有。其中TCFH−NMI一般是苯胺類的專屬。

TCFH-NMI的酸胺縮合通式

酸胺縮合反應機理

應用案例一

實驗操作
To reactor R1 was added 2 (2.24 kg, 11.5 mol, 1.00 equiv), 3 (4.19 kg, 13.8 mol,1.20 equiv), and NMP (28.1 kg). The reaction mixture was stirred for 5 min at 20−25 °C, and the reactor was then charged sequentially with 2,6-lutidine (2.54 kg, 23.0 mol, 2.00 equiv) and TCFH (4.26 kg, 15.0 mol, 1.30 equiv) at 20−30 °C. NMP (2.58 kg) was then added and the contents were stirred for 6 h at 20−30 °C until completion of the reaction (2≤1.0 A% HPLC).

應用案例二

實驗操作
A reactor was charged with N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate(TCFH) (95 kg, 1.25 equiv) and acetonitrile (237kg). N-Methylimidazole (69 kg, 3.10 equiv) was added followed by acetonitrile (32 kg). (R)-2-((1s,4s)-4-(6-Fluoroquinolin-4-yl)cyclohexyl)propanoic acid 2 (82.0 kg, 1.0equiv) was added followed by acetonitrile (63 kg). 
The mixture was held for 0.5 h, and then a solution of 4-chloroaniline (40 kg, 1.15 equiv) dissolved in acetonitrile (96 kg) was charged followed by acetonitrile (63 kg). The mixturewas maintained at 20 °C for 3 h

參考文獻

Org. Lett. 2018, 20, 4218−4222

Org. Process Res. Dev. 2021, 25, 2338−2350

Org. Process Res. Dev. 2019, 23, 2482−2498


案例三

  • 篩選過程發現，氯化亞碸條件（entry 2）和TCFH條件（entry 7）可以比擬最初的三氯氧磷/吡啶條件。
  • 對比氯化亞碸和TCFH條件，從釋放氣體的安全方面和後處理角度，選擇了後者TDFH

參考文獻
https://doi.org/10.1021/acs.oprd.3c00423

案例四
  • 第一代路線採用EDCI/HOBT，均採用1.6eq.，基於HOBT的安全風險，再次對縮合劑進行了篩選。
  • 採用DMAP代替HOBT（entry 1和2），無論催化量還是當量，轉化率都不錯，但是收率不是很高。
  • 採用TCFH（entry 5），轉化率非常高，收率也非常高。
參考文獻
https://doi.org/10.1021/acs.oprd.3c00446